A cell death avenue evolved from a life-saving path Harm H. Kampinga Science 344, 1341 (2014); DOI: 10.1126/science.1256084
This copy is for your personal, non-commercial use only.
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of June 19, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/344/6190/1341.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/344/6190/1341.full.html#related This article cites 11 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/344/6190/1341.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
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microscopy and modeling revealed oriented attachment through (001) facets. The honeycomb superlattices resemble atomic twodimensional crystals such as graphene or molybdenum disulfide and are remarkably robust: Lead ions may be exchanged for cadmium without disrupting the selenium anion lattice. How can such a complex structure form through attachment of nanocrystals that were originally separated by surface ligands? Given the similarity between PbSe and PbS, we can draw inspiration from the theoretical work of Zherebetskyy et al. For PbS nanocrystals, the binding energy of oleic acid to the (001) facet is too low to keep surfactant molecules in place for a long period of time. Binding of oleate/hydroxyl pairs to the (111) surface is much stronger. A simple calculation based on reported binding energies suggests that surfactants are less likely to desorb from a (111) surface than from a (001) surface by a factor of ~106. Furthermore, the ethylene glycol surface used by Boneschanscher et al. may not only act as the stage on which self-assembly takes place, but may also gently remove loosely bound (001) ligands from PbSe nanocrystals. In contrast, (111) surfaces remain protected by the oleate and hydroxyl ligands. Bare (001) facets become “sticky patches,” guiding the attachment of PbSe nanocrystals into buckled silicene-like two-dimensional sheets that may have exotic electronic properties (11). The work of Zherebetskyy et al. offers a new understanding of the nanocrystal surface and lays the foundation for targeted design of unusual nanocrystal architectures like that presented by Boneschanscher et al. Thoughtful use of surface ligands that bind strongly to some crystal facets and weakly to others may enable the construction of novel materials by merging crystalline particles through engineered surface patches (12). The first chapter of colloidal nanocrystal research was written by those who managed to tame the surface; the next challenge is to put it to work. ■
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
REFERENCES
1. D. Zherebetskyy et al., Science 344, 1380 (2014). 2. M. P. Boneschanscher et al, Science 344, 1377 (2014). 3. C. B. Murray, D. J. Norris, M. G. Bawendi, J. Am. Chem. Soc. 115, 8706 (1993). 4. J. C. Love, L. A. Estroff, J. K. Kriebel, R. G. Nuzzo, G. M. Whitesides, Chem. Rev. 105, 1103 (2005). 5. I. Moreels et al., ACS Nano 3, 3023 (2009). 6. R. L. Penn, J. F. Banfield, Science 281, 969 (1998). 7. Z. Tang, N. A. Kotov, M. Giersig, Science 297, 237 (2002). 8. K. S. Cho, D. V. Talapin, W. Gaschler, C. B. Murray, J. Am. Chem. Soc. 127, 7140 (2005). 9. C. Schliehe et al., Science 329, 550 (2010). 10. P. Vogt et al., Phys. Rev. Lett. 108, 155501 (2012). 11. E. Kalesaki et al., Phys. Rev. X 4, 011010 (2014). 12. Z. Zhang, S. C. Glotzer, Nano Lett. 4, 1407 (2004). 10.1126/science.1256197
CELL BIOLOGY
A cell death avenue evolved from a life-saving path Altruistic cell suicide model is challenged By Harm H. Kampinga
Y
east metacaspases are the ancestral enzymes of caspases that execute cellular suicide (“programmed cell death”) in multicellular organisms. Studies on metacaspase 1 (Mca1) have suggested that single-cell eukaryotes can also commit programmed cell death (1, 2). However, on page 1389 of this issue,
Malmgren Hill et al. (3) show that Mca1 has positive rather than negative effects on the life span of the budding yeast Saccharomyces cerevisiae, especially when protein homeostasis is impaired. Mca1 helps to degrade misfolded proteins that accumulate during aging or that are generated by acute stress, and thereby ensures the continuous and healthy generation of daughter cells that are free of insoluble aggregates that otherwise would limit life span. Loss of Mca1 activity has been associated with a reduced appearance of programmed cell death markers (1, 4), implying that its overexpression should decrease the replicative life span of yeast (the number of daughter cells a mother cell can produce throughout its life). Cells lacking Mca1 have increased amounts of protein aggregates and oxidized proteins (4, 5). Malmgren Hill et al.
SCIENCE sciencemag.org
not only show that this is related to decreased survival, but also provide mechanistic insights into the mode of action of Mca1. Its pro-life action depends on the chaperone heat shock protein 104 (Hsp104), a protein that can disentangle protein aggregates and is crucial for the asymmetric segregation of protein aggregates in dividing cells. Mca1 deficiency does not affect life span of wildtype strains, but further decreases life span
in strains already compromised in protein quality control. In particular, replicative aging is accelerated in strains lacking the Hsp70 co-chaperone Ydj1. Mca1 does not improve protein folding but supports degradation of terminally misfolded proteins. Malmgren Hill et al. show that Mca1 requires proteasomes (protein structures that break down proteins) for all its effects. The study by Malmgren Hill et al. challenges the idea that caspases are activated as an altruistic suicide mechanism in single-cell eukaryotes as a means to provide nutrients for younger and fitter cells in the population (2). Rather, the data sugDepartment of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. E-mail: [email protected] 20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
1341
INSIGHTS | P E R S P E C T I V E S
The results of Malmgren Hill et al. also highlight the importance of protein quality control for cellular aging. A collapse of protein homeostasis has been implicated mostly in chronological aging of differentiated cells and, for example, as a cause of neurodegenerative diseases (6). The authors show that it also plays a prominent role in replicative aging. This supports early findings in yeast (7) and may also be relevant to metazoa, in which stem cells have extremely efficient protein degradation mechanisms (8) and also use asymmetric segregation of protein damage for rejuvenation (9). The data of Malmgren Hill et al. also suggest the existence of an additional layer of control of protein homeostasis. Beyond the activation and induction of chaperones that assist in protein sorting, refolding, and
Polypeptide Str es s
Stress
Folded
Mis-/unfolded early aggregate Degradation
Proteasome Disaggregation
Aggregate
Disaggregation and fragmentation
Di sa
gg
reg atio
n an
d refolding
protein degradation via proteasomes and autophagosomes (membrane structures that deliver proteins to lysosomes for enzymatic destruction) (10), Malmgren Hill et al. show that activation of caspases also belongs to the cell’s repertoire of defense mechanisms against protein damage. Mca1 might act in parallel to the Ssa-Ydj1 machinery. Although Ssa-Ydj1 collaborates with Hsp104 to refold proteins after their aggregation (11), Mca1 primarily supports protein degradation, as its actions require not only Hsp104 but also proteasomal activity (3). Precisely how Mca1 exerts its effect is yet unclear. It can associate with aggregates independent of other chaperones (3, 5) and independent of its catalytic activity (5), suggesting that it binds directly to misfolded proteins [likely through its amino-terminal “pro-domain” that is rich in glutamine and asparagine repeats]. This interaction may exert chaperone-like activity by keeping unfolded proteins in a proteasome-competent form, which explains why part of Mca1’s protective actions in wild-type strains is independent of its protease activity. However, the caspase activity of Mca1 is required for protein homeostasis and control of life span in Ydj1-deficient strains. It could be that for more terminally misfolded proteins that accumulate in the absence of Ydj1, protease cleavage may help to dismantle such aggregates in concert with Ssa and Hsp104 (see the figure). This would also explain why the strongest phenotypes of Mca1 are seen under conditions in which Ydj1 is absent. More biochemical data with purified proteins will be needed to test these ideas. The study of Malmgren Hill et al. suggests that altruism may not exist among cells. However, life and death seem to be close neighbors, and the things that are life saving may also become lethal. It will therefore be a challenge to make use of these insights into caspase function in order to treat diseases by selectively tipping the balance toward life (e.g., in neurodegenerative diseases) or death (e.g., in cancer). ■ REFERENCES
1. 2. 3. 4. 5.
Hsp104
6.
Ssa Mca1
Ydj1 7.
Defense against protein damage. Stress-damaged proteins that form aggregates in cells can be reactivated with the Hsp104-Ssa-Ydj1 chaperone machinery. Mca1 may act in parallel by binding to misfolded proteins during early stages of aggregation for proteasomal degradation (this is independent of Mca1’s enzymatic activity). Alternatively, Mca1 may associate with misfolded proteins formed at late stages of aggregation (together with Hsp104 and Ssa), helping to disentangle the aggregates by its protease cleavage activity before shunting them to the proteasome for degradation.
1342
8. 9. 10. 11.
F. Madeo et al., Mol. Cell 9, 911 (2002). E. Herker et al., J. Cell Biol. 164, 501 (2004). S. Malmgren Hill et al., Science 344, 1389 (2014). M. A. Khan, P. B. Chock, E. R. Stadtman, Proc. Natl. Acad. Sci. U.S.A. 102, 17326 (2005). R. E. Lee, S. Brunette, L. G. Puente, L. A. Megeney, Proc. Natl. Acad. Sci. U.S.A. 107, 13348 (2010). W. E. Balch, R. I. Morimoto, A. Dillin, J. W. Kelly, Science 319, 916 (2008). H. Aguilaniu, L. Gustafsson, M. Rigoulet, T. Nyström, Science 299, 1751 (2003). D. Vilchez et al., Nature 489, 304 (2012). M. A. Rujano et al., PLOS Biol. 4, e417 (2006). H. H. Kampinga, E. A. Craig, Nat. Rev. Mol. Cell Biol. 11, 579 (2010). J. R. Glover, S. Lindquist, Cell 94, 73 (1998). 10.1126/science.1256084
sciencemag.org SCIENCE
20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
gest that from an evolutionary perspective, caspase activation is an integrated part of a protective response to help cells survive toxic stress caused by the accumulation of misfolded proteins. When, however, activated incorrectly (e.g., in the absence of proteotoxic stress) or too strongly (e.g., in the case of excessive damage to the cell), the caspase activity may become nonselective and thus lead to the typical Mca1dependent hallmarks of programmed cell death (1, 2, 4). Also, caspase activation in metazoa may function primarily in cell-autonomous protection and cellular remodeling or pruning. Its role in programmed cell death may also simply reflect overactivation upon severe cellular damage or hijacking of the caspases in the absence of stress to serve in non–cell-autonomous regulated tissue homeostasis.
This copy is for your personal, non-commercial use only.
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of June 19, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/344/6190/1341.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/344/6190/1341.full.html#related This article cites 11 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/344/6190/1341.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on June 19, 2014
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
microscopy and modeling revealed oriented attachment through (001) facets. The honeycomb superlattices resemble atomic twodimensional crystals such as graphene or molybdenum disulfide and are remarkably robust: Lead ions may be exchanged for cadmium without disrupting the selenium anion lattice. How can such a complex structure form through attachment of nanocrystals that were originally separated by surface ligands? Given the similarity between PbSe and PbS, we can draw inspiration from the theoretical work of Zherebetskyy et al. For PbS nanocrystals, the binding energy of oleic acid to the (001) facet is too low to keep surfactant molecules in place for a long period of time. Binding of oleate/hydroxyl pairs to the (111) surface is much stronger. A simple calculation based on reported binding energies suggests that surfactants are less likely to desorb from a (111) surface than from a (001) surface by a factor of ~106. Furthermore, the ethylene glycol surface used by Boneschanscher et al. may not only act as the stage on which self-assembly takes place, but may also gently remove loosely bound (001) ligands from PbSe nanocrystals. In contrast, (111) surfaces remain protected by the oleate and hydroxyl ligands. Bare (001) facets become “sticky patches,” guiding the attachment of PbSe nanocrystals into buckled silicene-like two-dimensional sheets that may have exotic electronic properties (11). The work of Zherebetskyy et al. offers a new understanding of the nanocrystal surface and lays the foundation for targeted design of unusual nanocrystal architectures like that presented by Boneschanscher et al. Thoughtful use of surface ligands that bind strongly to some crystal facets and weakly to others may enable the construction of novel materials by merging crystalline particles through engineered surface patches (12). The first chapter of colloidal nanocrystal research was written by those who managed to tame the surface; the next challenge is to put it to work. ■
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
REFERENCES
1. D. Zherebetskyy et al., Science 344, 1380 (2014). 2. M. P. Boneschanscher et al, Science 344, 1377 (2014). 3. C. B. Murray, D. J. Norris, M. G. Bawendi, J. Am. Chem. Soc. 115, 8706 (1993). 4. J. C. Love, L. A. Estroff, J. K. Kriebel, R. G. Nuzzo, G. M. Whitesides, Chem. Rev. 105, 1103 (2005). 5. I. Moreels et al., ACS Nano 3, 3023 (2009). 6. R. L. Penn, J. F. Banfield, Science 281, 969 (1998). 7. Z. Tang, N. A. Kotov, M. Giersig, Science 297, 237 (2002). 8. K. S. Cho, D. V. Talapin, W. Gaschler, C. B. Murray, J. Am. Chem. Soc. 127, 7140 (2005). 9. C. Schliehe et al., Science 329, 550 (2010). 10. P. Vogt et al., Phys. Rev. Lett. 108, 155501 (2012). 11. E. Kalesaki et al., Phys. Rev. X 4, 011010 (2014). 12. Z. Zhang, S. C. Glotzer, Nano Lett. 4, 1407 (2004). 10.1126/science.1256197
CELL BIOLOGY
A cell death avenue evolved from a life-saving path Altruistic cell suicide model is challenged By Harm H. Kampinga
Y
east metacaspases are the ancestral enzymes of caspases that execute cellular suicide (“programmed cell death”) in multicellular organisms. Studies on metacaspase 1 (Mca1) have suggested that single-cell eukaryotes can also commit programmed cell death (1, 2). However, on page 1389 of this issue,
Malmgren Hill et al. (3) show that Mca1 has positive rather than negative effects on the life span of the budding yeast Saccharomyces cerevisiae, especially when protein homeostasis is impaired. Mca1 helps to degrade misfolded proteins that accumulate during aging or that are generated by acute stress, and thereby ensures the continuous and healthy generation of daughter cells that are free of insoluble aggregates that otherwise would limit life span. Loss of Mca1 activity has been associated with a reduced appearance of programmed cell death markers (1, 4), implying that its overexpression should decrease the replicative life span of yeast (the number of daughter cells a mother cell can produce throughout its life). Cells lacking Mca1 have increased amounts of protein aggregates and oxidized proteins (4, 5). Malmgren Hill et al.
SCIENCE sciencemag.org
not only show that this is related to decreased survival, but also provide mechanistic insights into the mode of action of Mca1. Its pro-life action depends on the chaperone heat shock protein 104 (Hsp104), a protein that can disentangle protein aggregates and is crucial for the asymmetric segregation of protein aggregates in dividing cells. Mca1 deficiency does not affect life span of wildtype strains, but further decreases life span
in strains already compromised in protein quality control. In particular, replicative aging is accelerated in strains lacking the Hsp70 co-chaperone Ydj1. Mca1 does not improve protein folding but supports degradation of terminally misfolded proteins. Malmgren Hill et al. show that Mca1 requires proteasomes (protein structures that break down proteins) for all its effects. The study by Malmgren Hill et al. challenges the idea that caspases are activated as an altruistic suicide mechanism in single-cell eukaryotes as a means to provide nutrients for younger and fitter cells in the population (2). Rather, the data sugDepartment of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. E-mail: [email protected] 20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
1341
INSIGHTS | P E R S P E C T I V E S
The results of Malmgren Hill et al. also highlight the importance of protein quality control for cellular aging. A collapse of protein homeostasis has been implicated mostly in chronological aging of differentiated cells and, for example, as a cause of neurodegenerative diseases (6). The authors show that it also plays a prominent role in replicative aging. This supports early findings in yeast (7) and may also be relevant to metazoa, in which stem cells have extremely efficient protein degradation mechanisms (8) and also use asymmetric segregation of protein damage for rejuvenation (9). The data of Malmgren Hill et al. also suggest the existence of an additional layer of control of protein homeostasis. Beyond the activation and induction of chaperones that assist in protein sorting, refolding, and
Polypeptide Str es s
Stress
Folded
Mis-/unfolded early aggregate Degradation
Proteasome Disaggregation
Aggregate
Disaggregation and fragmentation
Di sa
gg
reg atio
n an
d refolding
protein degradation via proteasomes and autophagosomes (membrane structures that deliver proteins to lysosomes for enzymatic destruction) (10), Malmgren Hill et al. show that activation of caspases also belongs to the cell’s repertoire of defense mechanisms against protein damage. Mca1 might act in parallel to the Ssa-Ydj1 machinery. Although Ssa-Ydj1 collaborates with Hsp104 to refold proteins after their aggregation (11), Mca1 primarily supports protein degradation, as its actions require not only Hsp104 but also proteasomal activity (3). Precisely how Mca1 exerts its effect is yet unclear. It can associate with aggregates independent of other chaperones (3, 5) and independent of its catalytic activity (5), suggesting that it binds directly to misfolded proteins [likely through its amino-terminal “pro-domain” that is rich in glutamine and asparagine repeats]. This interaction may exert chaperone-like activity by keeping unfolded proteins in a proteasome-competent form, which explains why part of Mca1’s protective actions in wild-type strains is independent of its protease activity. However, the caspase activity of Mca1 is required for protein homeostasis and control of life span in Ydj1-deficient strains. It could be that for more terminally misfolded proteins that accumulate in the absence of Ydj1, protease cleavage may help to dismantle such aggregates in concert with Ssa and Hsp104 (see the figure). This would also explain why the strongest phenotypes of Mca1 are seen under conditions in which Ydj1 is absent. More biochemical data with purified proteins will be needed to test these ideas. The study of Malmgren Hill et al. suggests that altruism may not exist among cells. However, life and death seem to be close neighbors, and the things that are life saving may also become lethal. It will therefore be a challenge to make use of these insights into caspase function in order to treat diseases by selectively tipping the balance toward life (e.g., in neurodegenerative diseases) or death (e.g., in cancer). ■ REFERENCES
1. 2. 3. 4. 5.
Hsp104
6.
Ssa Mca1
Ydj1 7.
Defense against protein damage. Stress-damaged proteins that form aggregates in cells can be reactivated with the Hsp104-Ssa-Ydj1 chaperone machinery. Mca1 may act in parallel by binding to misfolded proteins during early stages of aggregation for proteasomal degradation (this is independent of Mca1’s enzymatic activity). Alternatively, Mca1 may associate with misfolded proteins formed at late stages of aggregation (together with Hsp104 and Ssa), helping to disentangle the aggregates by its protease cleavage activity before shunting them to the proteasome for degradation.
1342
8. 9. 10. 11.
F. Madeo et al., Mol. Cell 9, 911 (2002). E. Herker et al., J. Cell Biol. 164, 501 (2004). S. Malmgren Hill et al., Science 344, 1389 (2014). M. A. Khan, P. B. Chock, E. R. Stadtman, Proc. Natl. Acad. Sci. U.S.A. 102, 17326 (2005). R. E. Lee, S. Brunette, L. G. Puente, L. A. Megeney, Proc. Natl. Acad. Sci. U.S.A. 107, 13348 (2010). W. E. Balch, R. I. Morimoto, A. Dillin, J. W. Kelly, Science 319, 916 (2008). H. Aguilaniu, L. Gustafsson, M. Rigoulet, T. Nyström, Science 299, 1751 (2003). D. Vilchez et al., Nature 489, 304 (2012). M. A. Rujano et al., PLOS Biol. 4, e417 (2006). H. H. Kampinga, E. A. Craig, Nat. Rev. Mol. Cell Biol. 11, 579 (2010). J. R. Glover, S. Lindquist, Cell 94, 73 (1998). 10.1126/science.1256084
sciencemag.org SCIENCE
20 JUNE 2014 • VOL 344 ISSUE 6190
Published by AAAS
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
gest that from an evolutionary perspective, caspase activation is an integrated part of a protective response to help cells survive toxic stress caused by the accumulation of misfolded proteins. When, however, activated incorrectly (e.g., in the absence of proteotoxic stress) or too strongly (e.g., in the case of excessive damage to the cell), the caspase activity may become nonselective and thus lead to the typical Mca1dependent hallmarks of programmed cell death (1, 2, 4). Also, caspase activation in metazoa may function primarily in cell-autonomous protection and cellular remodeling or pruning. Its role in programmed cell death may also simply reflect overactivation upon severe cellular damage or hijacking of the caspases in the absence of stress to serve in non–cell-autonomous regulated tissue homeostasis.
